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minigenome-based reporter system suitable for high-throughput screening of compounds able to inhibit ebolavirus replication and/or transcription.we describe an ebolavirus minigenome-based system that is suitable for high-throughput screening of compounds able to impair ebolavirus virus replication and/or transcription. the assay is robust (z' factor, >0.6) and can be carried out in low-biosafety containment. results from a pilot screen of 960 compounds are presented.201020421407
both matrix proteins of ebola virus contribute to the regulation of viral genome replication and transcription.ebola virus (ebov) causes severe hemorrhagic fevers in humans and non-human primates. while the role of the ebov major matrix protein vp40 in morphogenesis is well understood, nothing is known about its contributions to the regulation of viral genome replication and/or transcription. similarly, while it was reported that the minor matrix protein vp24 impairs viral genome replication, it remains unclear whether it also regulates transcription, since all common experimental systems measure the com ...201020444481
ebola virus glycoprotein counteracts bst-2/tetherin restriction in a sequence-independent manner that does not require tetherin surface removal.bst-2/tetherin is an interferon-inducible protein that restricts the release of enveloped viruses from the surface of infected cells by physically linking viral and cellular membranes. it is present at both the cell surface and in a perinuclear region, and viral anti-tetherin factors including hiv-1 vpu and hiv-2 env have been shown to decrease the cell surface population. to map the domains of human tetherin necessary for both virus restriction and sensitivity to viral anti-tetherin factors, we ...201020444895
anti-ebola mab 17a3 reacts with bovine and human alpha-2-macroglobulin proteins.monoclonal antibodies (mabs) were developed against soluble ebola virus (ebov) envelope glycoprotein (gp) for the study of the diversity of ebov envelope and development of diagnostic reagents. of the three anti-ebov gp mouse mabs produced, mab 15h10 recognized all human ebov gp species tested (zaire, sudan, ivory coast), and as well as reacted with the reston nonhuman primate ebov gps. a second mab, 6d11 recognized ebov gp species of sudan and sudan-gulu. the third mab, 17a3, was reported origi ...201020447422
inhibition of heat-shock protein 90 reduces ebola virus replication.ebola virus (ebov), a negative-sense rna virus in the family filoviridae, is known to cause severe hemorrhagic fever in humans and other primates. infection with ebov causes a high mortality rate and currently there is no fda-licensed vaccine or therapeutic treatment available. recently, heat-shock protein 90 (hsp90), a molecular chaperone, was shown to be an important host factor for the replication of several negative-strand viruses. we tested the effect of several different hsp90 inhibitors i ...201020452380
effects of the usa patriot act and the 2002 bioterrorism preparedness act on select agent research in the united states.a bibliometric analysis of the bacillus anthracis and ebola virus archival literature was conducted to determine whether negative consequences of the uniting and strengthening america by providing appropriate tools required to intercept and obstruct terrorism" (usa patriot) act and the 2002 bioterrorism preparedness act on us select agent research could be discerned. indicators of the health of the field, such as number of papers published per year, number of researchers authoring papers, and in ...201020457912
oligomerization of ebola virus vp40 is essential for particle morphogenesis and regulation of viral transcription.the morphogenesis and budding of virus particles represent an important stage in the life cycle of viruses. for ebola virus, this process is driven by its major matrix protein, vp40. like the matrix proteins of many other nonsegmented, negative-strand rna viruses, vp40 has been demonstrated to oligomerize and to occur in at least two distinct oligomeric states: hexamers and octamers, which are composed of antiparallel dimers. while it has been shown that vp40 oligomers are essential for the vira ...201020463076
demonstration of cross-protective vaccine immunity against an emerging pathogenic ebolavirus species.a major challenge in developing vaccines for emerging pathogens is their continued evolution and ability to escape human immunity. therefore, an important goal of vaccine research is to advance vaccine candidates with sufficient breadth to respond to new outbreaks of previously undetected viruses. ebolavirus (ebov) vaccines have demonstrated protection against ebov infection in nonhuman primates (nhp) and show promise in human clinical trials but immune protection occurs only with vaccines whose ...201020502688
postexposure protection of non-human primates against a lethal ebola virus challenge with rna interference: a proof-of-concept study.we previously showed that small interfering rnas (sirnas) targeting the zaire ebola virus (zebov) rna polymerase l protein formulated in stable nucleic acid-lipid particles (snalps) completely protected guineapigs when administered shortly after a lethal zebov challenge. although rodent models of zebov infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. we therefore assessed the ...201020511019
a novel l-ficolin/mannose-binding lectin chimeric molecule with enhanced activity against ebola virus.ebola viruses constitute a newly emerging public threat because they cause rapidly fatal hemorrhagic fevers for which no treatment exists, and they can be manipulated as bioweapons. we targeted conserved n-glycosylated carbohydrate ligands on viral envelope surfaces using novel immune therapies. mannose-binding lectin (mbl) and l-ficolin (l-fcn) were selected because they function as opsonins and activate complement. given that mbl has a complex quaternary structure unsuitable for large scale co ...201020516066
crystallization and preliminary x-ray analysis of ebola vp35 interferon inhibitory domain mutant proteins.vp35 is one of seven structural proteins encoded by the ebola viral genome and mediates viral replication, nucleocapsid formation and host immune suppression. the c-terminal interferon inhibitory domain (iid) of vp35 is critical for dsrna binding and interferon inhibition. the wild-type vp35 iid structure revealed several conserved residues that are important for dsrna binding and interferon antagonism. here, the expression, purification and crystallization of recombinant zaire ebola vp35 iid mu ...201020516601
bad wraps on viruses. 201020521472
the survival of filoviruses in liquids, on solid substrates and in a dynamic aerosol.filoviruses are associated with high morbidity and lethality rates in humans, are capable of human-to-human transmission, via infected material such as blood, and are believed to have low infectious doses for humans. filoviruses are able to infect via the respiratory route and are lethal at very low doses in experimental animal models, but there is minimal information on how well the filoviruses survive within aerosol particles. there is also little known about how well filoviruses survive in li ...201020553340
filoviruses are ancient and integrated into mammalian genomes.hemorrhagic diseases from ebolavirus and marburgvirus (filoviridae) infections can be dangerous to humans because of high fatality rates and a lack of effective treatments or vaccine. although there is evidence that wild mammals are infected by filoviruses, the biology of host-filovirus systems is notoriously poorly understood. specifically, identifying potential reservoir species with the expected long-term coevolutionary history of filovirus infections has been intractable. integrated elements ...201020569424
ebola hemorrhagic fever associated with novel virus strain, uganda, 2007-2008.during august 2007-february 2008, the novel bundibugyo ebolavirus species was identified during an outbreak of ebola viral hemorrhagic fever in bundibugyo district, western uganda. to characterize the outbreak as a requisite for determining response, we instituted a case-series investigation. we identified 192 suspected cases, of which 42 (22%) were laboratory positive for the novel species; 74 (38%) were probable, and 77 (40%) were negative. laboratory confirmation lagged behind outbreak verifi ...201020587179
experimental rna therapy shows promise against ebola virus in monkey studies. 201020606143
development of high-content imaging assays for lethal viral pathogens.filoviruses such as ebola (ebov) and marburg (marv) are single-stranded negative sense rna viruses that cause acute hemorrhagic fever with high mortality rates. currently, there are no licensed vaccines or therapeutics to counter filovirus infections in humans. the development of higher throughput/high-content primary screening assays followed by validation using the low-throughput traditional plaque or real-time pcr assays will greatly aid efforts toward the discovery of novel antiviral therape ...201020639507
genetic factors of ebola virus virulence in guinea pigs.zaire ebolavirus (zebov) causes severe hemorrhagic fever in primates, whereas in guinea pigs it induces a nonlethal infection with a mild fever and subsequent recovery. we performed 7 selective passages in guinea pigs resulted in obtaining of guinea pig-adapted strain (gpa-p7) strain. by the 7th passage, the infection with ebov induced a lethal disease in animals accompanied by the characteristic hematological changes: leukocytosis (primarily due to neutrophilia) as well as pronounced deficienci ...201020654661
prospects for immunisation against marburg and ebola viruses.for more than 30 years the filoviruses, marburg virus and ebola virus, have been associated with periodic outbreaks of hemorrhagic fever that produce severe and often fatal disease. the filoviruses are endemic primarily in resource-poor regions in central africa and are also potential agents of bioterrorism. although no vaccines or antiviral drugs for marburg or ebola are currently available, remarkable progress has been made over the last decade in developing candidate preventive vaccines again ...201020658513
recent advances in ebolavirus vaccine development.ebolavirus is a highly infectious pathogen with a case fatality rate as high as 90%. currently there is a lack of licensed ebolavirus vaccines as well as pre- and post-exposure treatments. recent increases in the frequency of natural human ebolavirus infections and its potential use as a bioterrorism agent makes vaccine development a priority for many nations. significant progress has been made in understanding the pathogenesis of ebolavirus infection and several promising vaccine candidates wer ...201020671437
basic residues within the ebolavirus vp35 protein are required for its viral polymerase cofactor function.the ebolavirus (ebov) vp35 protein binds to double-stranded rna (dsrna), inhibits host alpha/beta interferon (ifn-α/β) production, and is an essential component of the viral polymerase complex. structural studies of the vp35 c-terminal ifn inhibitory domain (iid) identified specific structural features, including a central basic patch and a hydrophobic pocket, that are important for dsrna binding and ifn inhibition. several other conserved basic residues bordering the central basic patch and a s ...201020686031
infectious lassa virus, but not filoviruses, is restricted by bst-2/tetherin.bone marrow stromal antigen 2 (bst-2/tetherin) is a cellular membrane protein that inhibits the release of hiv-1. we show for the first time, using infectious viruses, that bst-2 also inhibits egress of arenaviruses but has no effect on filovirus replication and spread. specifically, infectious lassa virus (lasv) release significantly decreased or increased in human cells in which bst-2 was either stably expressed or knocked down, respectively. in contrast, replication and spread of infectious z ...201020686043
unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.vertebrate genomes contain numerous copies of retroviral sequences, acquired over the course of evolution. until recently they were thought to be the only type of rna viruses to be so represented, because integration of a dna copy of their genome is required for their replication. in this study, an extensive sequence comparison was conducted in which 5,666 viral genes from all known non-retroviral families with single-stranded rna genomes were matched against the germline genomes of 48 vertebrat ...201020686665
long-term survival of an urban fruit bat seropositive for ebola and lagos bat viruses.ebolaviruses (ebov) (family filoviridae) cause viral hemorrhagic fevers in humans and non-human primates when they spill over from their wildlife reservoir hosts with case fatality rates of up to 90%. fruit bats may act as reservoirs of the filoviridae. the migratory fruit bat, eidolon helvum, is common across sub-saharan africa and lives in large colonies, often situated in cities. we screened sera from 262 e. helvum using indirect fluorescent tests for antibodies against ebov subtype zaire. we ...201020694141
identification of essential filovirion-associated host factors by serial proteomic analysis and rnai screen.an assessment of the total protein composition of filovirus (ebolavirus and marburgvirus) virions is currently lacking. in this study, liquid chromatography-linked tandem mass spectrometry of purified ebola and marburg virions was performed to identify associated cellular proteins. host proteins involved in cell adhesion, cytoskeleton, cell signaling, intracellular trafficking, membrane organization, and chaperones were identified. significant overlap exists between this data set and proteomic s ...201020702783
advanced antisense therapies for postexposure protection against lethal filovirus infections.currently, no vaccines or therapeutics are licensed to counter ebola or marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. here we show that administration of positively charged phosphorodiamidate morpholino oligomers (pmoplus), delivered by various dosing strategies initiated 30-60 min after infection, protects>60% of rhesus monkeys against lethal zaire ebola virus (zebov) and 100% of cynomolgus monkeys against lake victoria marburg virus (marv) ...201020729866
cross-platform evaluation of commercial real-time reverse transcription pcr master mix kits using a quantitative 5'nuclease assay for ebola virus.selection of optimal reaction master mix reagents is essential to obtain the best performance with diagnostic real-time reverse transcription polymerase chain reaction (rt-pcr) assays. every year the number of commercially available master mix kits increases, so it is prudent to periodically evaluate kits on the market. in this study we evaluated five commercial real-time rt-pcr master mix kits, the realmastermix rt-pcr rox kit, the agpath-id one-step rt-pcr kit, the superscript iii platinum one ...201020732412
establishment of fruit bat cells (rousettus aegyptiacus) as a model system for the investigation of filoviral infection.the fruit bat species rousettus aegyptiacus was identified as a potential reservoir for the highly pathogenic filovirus marburg virus. to establish a basis for a molecular understanding of the biology of filoviruses in the reservoir host, we have adapted a set of molecular tools for investigation of filovirus replication in a recently developed cell line, r06e, derived from the species rousettus aegyptiacus.201020808767
cell adhesion-dependent membrane trafficking of a binding partner for the ebolavirus glycoprotein is a determinant of viral entry.ebolavirus is a hemorrhagic fever virus associated with high mortality. although much has been learned about the viral lifecycle and pathogenesis, many questions remain about virus entry. we recently showed that binding of the receptor binding region (rbr) of the ebolavirus glycoprotein (gp) and infection by gp pseudovirions increase on cell adhesion independently of mrna or protein synthesis. one model to explain these observations is that, on cell adhesion, an rbr binding partner translocates ...201020817853
persistence in darkness of virulent alphaviruses, ebola virus, and lassa virus deposited on solid surfaces.ebola, lassa, venezuelan equine encephalitis, and sindbis viruses were dried onto solid surfaces, incubated for various time periods under controlled conditions of temperature and relative humidity, and quantitatively eluted from surfaces, and viral titers in the recovered samples were determined. the viral inactivation kinetics that were obtained indicated that viral resistance to natural inactivation in the dark follows (in decreasing order of stability) alphavirus > lassa virus > ebola virus. ...201020842393
steric shielding of surface epitopes and impaired immune recognition induced by the ebola virus glycoprotein.many viruses alter expression of proteins on the surface of infected cells including molecules important for immune recognition, such as the major histocompatibility complex (mhc) class i and ii molecules. virus-induced downregulation of surface proteins has been observed to occur by a variety of mechanisms including impaired transcription, blocks to synthesis, and increased turnover. viral infection or transient expression of the ebola virus (ebov) glycoprotein (gp) was previously shown to resu ...201020844579
enzyme-linked immunosorbent assay for detection of filovirus species-specific antibodies.several enzyme-linked immunosorbent assays (elisas) for the detection of filovirus-specific antibodies have been developed. however, diagnostic methods to distinguish antibodies specific to the respective species of filoviruses, which provide the basis for serological classification, are not readily available. we established an elisa using his-tagged secreted forms of the transmembrane glycoproteins (gps) of five different ebola virus (ebov) species and one marburg virus (marv) strain as antigen ...201020861331
cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.zaire ebolavirus (zebov), a highly pathogenic zoonotic virus, poses serious public health, ecological and potential bioterrorism threats. currently no specific therapy or vaccine is available. virus entry is an attractive target for therapeutic intervention. however, current knowledge of the zebov entry mechanism is limited. while it is known that zebov enters cells through endocytosis, which of the cellular endocytic mechanisms used remains unclear. previous studies have produced differing outc ...201020862315
association of kir2ds1 and kir2ds3 with fatal outcome in ebola virus infection.zaïre ebolavirus (zebov) infection rapidly outruns the host's immunity and leads to death within a week. fatal cases have been associated with an aberrant innate, proinflammatory immune response followed by a suppressed adaptive response leading to the rapid depletion of peripheral nk cells and lymphocytes. a critical role for nk cells has been suggested but not elucidated. in this genetic study, we investigated the association of kir genotype with disease outcome by comparing genotypes of a gab ...201020878400
ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner.ebolavirus (ebov) is an enveloped, single-stranded, negative-sense rna virus that causes severe hemorrhagic fever with mortality rates of up to 90% in humans and nonhuman primates. previous studies suggest roles for clathrin- or caveolae-mediated endocytosis in ebov entry; however, ebolavirus virions are long, filamentous particles that are larger than the plasma membrane invaginations that characterize clathrin- or caveolae-mediated endocytosis. the mechanism of ebov entry remains, therefore, p ...201020886108
[evaluation of ebola virus reproduction in adult icr white mice].the investigators studied the ability of adult icr mice (a laboratory model that was most approximated to the wildtype populations of mice) to maintain ebola virus (ev) reproduction in the organism. the adult icr mice inoculated with ev during 23 passages were shown to maintain viral reproduction in the liver. the elevated levels of platelets and the early generation of fibrin and fibrinogen degradation products suggested there were hemostatic changes that did not, however, progress to severe co ...201020886711
human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis.ebolavirus species zaire (zebov) causes highly lethal hemorrhagic fever, resulting in the death of 90% of patients within days. most information on immune responses to zebov comes from in vitro studies and animal models. the paucity of data on human immune responses to this virus is mainly due to the fact that most outbreaks occur in remote areas. published studies in this setting, based on small numbers of samples and limited panels of immunological markers, have given somewhat different result ...201020957152
[treatment of ebola infection with sirna.]. 201020967928
respiratory tract immunization of non-human primates with a newcastle disease virus-vectored vaccine candidate against ebola virus elicits a neutralizing antibody response.we previously developed a respiratory tract vaccine candidate against ebola virus (ebov) based on human parainfluenza virus type 3 (hpiv3), a respiratory paramyxovirus, expressing the ebov gp envelope protein (hpiv3/gp) from an added gene. two doses of this vaccine candidate delivered by the intranasal and intratracheal route protected monkeys against intraperitoneal challenge with ebov; however, concerns exist that the vaccine candidate may have reduced immunogenicity in the adult human populat ...201021034822
a replication defective recombinant ad5 vaccine expressing ebola virus gp is safe and immunogenic in healthy adults.ebola virus causes irregular outbreaks of severe hemorrhagic fever in equatorial africa. case mortality remains high; there is no effective treatment and outbreaks are sporadic and unpredictable. studies of ebola virus vaccine platforms in non-human primates have established that the induction of protective immunity is possible and safety and human immunogenicity has been demonstrated in a previous phase i clinical trial of a 1st generation ebola dna vaccine. we now report the safety and immunog ...201021034824
proposal for a revised taxonomy of the family filoviridae: classification, names of taxa and viruses, and virus abbreviations.the taxonomy of the family filoviridae (marburgviruses and ebolaviruses) has changed several times since the discovery of its members, resulting in a plethora of species and virus names and abbreviations. the current taxonomy has only been partially accepted by most laboratory virologists. confusion likely arose for several reasons: species names that consist of several words or which (should) contain diacritical marks, the current orthographic identity of species and virus names, and the simila ...201021046175
the tyro3 receptor kinase axl enhances macropinocytosis of zaire ebolavirus.axl, a plasma membrane-associated tyro3/axl/mer (tam) family member, is necessary for optimal zaire ebolavirus (zebov) glycoprotein (gp)-dependent entry into some permissive cells but not others. to date, the role of axl in virion entry is unknown. the focus of this study was to characterize entry pathways that are used for zebov uptake in cells that require axl for optimal transduction and to define the role of axl in this process. through the use of biochemical inhibitors, interfering rna (rna ...201021047970
towards broad protection against ebolaviruses.the ebola and marburg viruses (from the filovirus family) induce deadly hemorrhagic fevers for which there is currently no licensed vaccine or treatment. frequent outbreaks have occurred in sub-saharan africa, in humans and nonhuman primates over the last 15 years or so and constitute a major public health problem. of particular concern, a new species of ebolavirus recently emerged in uganda, highlighting the high potential of these viruses to evolve and the need to develop 'broad-spectrum' vacc ...201021073307
sensitivity to ultraviolet radiation of lassa, vaccinia, and ebola viruses dried on surfaces.germicidal uv (also known as uvc) provides a means to decontaminate infected environments as well as a measure of viral sensitivity to sunlight. the present study determined uvc inactivation slopes (and derived d(37) values) of viruses dried onto nonporous (glass) surfaces. the data obtained indicate that the uv resistance of lassa virus is higher than that of ebola virus. the uv sensitivity of vaccinia virus (a surrogate for variola virus) appeared intermediate between that of the two virulent ...201021104283
proportion of deaths and clinical features in bundibugyo ebola virus infection, uganda.the first known ebola hemorrhagic fever (ehf) outbreak caused by bundibugyo ebola virus occurred in bundibugyo district, uganda, in 2007. fifty-six cases of ehf were laboratory confirmed. although signs and symptoms were largely nonspecific and similar to those of ehf outbreaks caused by zaire and sudan ebola viruses, proportion of deaths among those infected was lower (≈40%).201021122234
progress in filovirus vaccine development: evaluating the potential for clinical use.marburg and ebola viruses cause severe hemorrhagic fever in humans and nonhuman primates. currently, there are no effective treatments and no licensed vaccines; although a number of vaccine platforms have proven successful in animal models. the ideal filovirus vaccine candidate should be able to provide rapid protection following a single immunization, have the potential to work postexposure and be cross-reactive or multivalent against all marburg virus strains and all relevant ebola virus speci ...201121162622
ebolavirus vp35 is a multifunctional virulence factor.ebola virus (ebov) is a member of the filoviridae family that causes severe hemorrhagic fever during sporadic outbreaks, and no approved treatments are currently available. the multifunctional ebov vp35 protein facilitates immune evasion by antagonizing antiviral signaling pathways and is important for viral rna synthesis. in order to elucidate regulatory mechanisms and to develop countermeasures, we recently solved the structures of the zaire and reston ebov vp35 interferon inhibitory domain (i ...201021178490
full-length ebola glycoprotein accumulates in the endoplasmic reticulum.the filoviridae family comprises of ebola and marburg viruses, which are known to cause lethal hemorrhagic fever. however, there is no effective anti-viral therapy or licensed vaccines currently available for these human pathogens. the envelope glycoprotein (gp) of ebola virus, which mediates entry into target cells, is cytotoxic and this effect maps to a highly glycosylated mucin-like region in the surface subunit of gp (gp1). however, the mechanism underlying this cytotoxic property of gp is u ...201121223600
ebolavirus proteins suppress the effects of small interfering rna by direct interaction with the mammalian rna interference pathway.cellular rna interference (rnai) provides a natural response against viral infection, but some viruses have evolved mechanisms to antagonize this form of antiviral immunity. to determine whether ebolavirus (ebov) counters rnai by encoding suppressors of rna silencing (srss), we screened all ebov proteins using an rnai assay initiated by exogenously delivered small interfering rnas (sirnas) against either an ebov or a reporter gene. in addition to viral protein 35 (vp35), we found that vp30 and v ...201121228243
effect of flanking residues on the conformational sampling of the internal fusion peptide from ebola virus.fusion peptides mediate viral and host-cell membrane fusion during viral entry. the monomeric form of the internal fusion peptide from ebola virus was studied in membrane bilayer and water environments with computer simulations using replica exchange sampling and an implicit solvent description of the environment. wild-type ebola fusion peptide (efp), the w8a mutant form, and an extended construct with flanking residues were examined. it was found that the monomeric form of wild-type efp adopts ...201121246633
measuring the strength of interaction between the ebola fusion peptide and lipid rafts: implications for membrane fusion and virus infection.the ebola fusion peptide (ebo₁₆) is a hydrophobic domain that belongs to the gp2 membrane fusion protein of the ebola virus. it adopts a helical structure in the presence of mimetic membranes that is stabilized by the presence of an aromatic-aromatic interaction established by trp8 and phe12. in spite of its infectious cycle becoming better understood recently, several steps still remain unclear, a lacuna that makes it difficult to develop strategies to block infection. in order to gain insight ...201121249196
mouse lsectin as a model for a human ebola virus receptor.the biochemical properties of mouse lsectin, a glycan-binding receptor that is a member of the c-type lectin family found on sinusoidal endothelial cells, have been investigated. the c-type carbohydrate-recognition domain of mouse lsectin, expressed in bacteria, has been used in solid-phase binding assays, and a tetramerized form has been used to probe a glycan array. in spite of sequence differences near the glycan-binding sites, the mouse receptor closely mimics the properties of the human rec ...201121257728
ebolavirus vp35 suppresses ifn production from conventional but not plasmacytoid dendritic cells.ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (dcs), and the resulting cytokine and interferon-a/ß (ifn) responses of infected cells are thought to influence viral pathogenesis. the vp35 protein impairs rig-i-like receptor-dependent signaling to inhibit ifn production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. to assess the impact of vp35 on innate immunity in biol ...201121263462
a chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype a light chain, p. falciparum malaria, and the ebola filovirus.a 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype a light chain metalloprotease. subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the bont/a lc. three-dimensional analyses indicated that half of the originally discovered 1,7-daac structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents. thi ...201121265542
identification of a small-molecule entry inhibitor for filoviruses.ebola virus (ebov) causes severe hemorrhagic fever, for which therapeutic options are not available. preventing the entry of ebov into host cells is an attractive antiviral strategy, which has been validated for hiv by the fda approval of the anti-hiv drug enfuvirtide. to identify inhibitors of ebov entry, the ebov envelope glycoprotein (ebov-gp) gene was used to generate pseudotype viruses for screening of chemical libraries. a benzodiazepine derivative (compound 7) was identified from a high-t ...201121270170
expression of an immunogenic ebola immune complex in nicotiana benthamiana.filoviruses (ebola and marburg viruses) cause severe and often fatal haemorrhagic fever in humans and non-human primates. the us centers for disease control identifies ebola and marburg viruses as 'category a' pathogens (defined as posing a risk to national security as bioterrorism agents), which has lead to a search for vaccines that could prevent the disease. because the use of such vaccines would be in the service of public health, the cost of production is an important component of their dev ...201121281425
high-dose mannose-binding lectin therapy for ebola virus infection.mannose-binding lectin (mbl) targets diverse microorganisms for phagocytosis and complement-mediated lysis by binding specific surface glycans. although recombinant human mbl (rhmbl) trials have focused on reconstitution therapy, safety studies have identified no barriers to its use at higher levels. ebola viruses cause fatal hemorrhagic fevers for which no treatment exists and that are feared as potential biothreat agents. we found that mice whose rhmbl serum concentrations were increased =7-fo ...201121288816
evidence for ebola virus superantigen activity. 201121307193
recombinant adenovirus serotype 26 (ad26) and ad35 vaccine vectors bypass immunity to ad5 and protect nonhuman primates against ebolavirus challenge.the use of adenoviruses (ad) as vaccine vectors against a variety of pathogens has demonstrated their capacity to elicit strong antibody and cell-mediated immune responses. adenovirus serotype c vectors, such as ad serotype 5 (ad5), expressing ebolavirus (ebov) glycoprotein (gp), protect completely after a single inoculation at a dose of 10(10) viral particles. however, the clinical application of a vaccine based on ad5 vectors may be hampered, since impairment of ad5 vaccine efficacy has been d ...201121325402
ebola virus glycoprotein fc fusion protein confers protection against lethal challenge in vaccinated mice.ebola virus is a filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. filoviruses are classified as "category a bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. the filovirus glycoprotein (gp) is sufficient to protect individuals against infection, and several vaccines based on gp are under development including recombinant adenovirus, parainfluenza virus, venezuelan equine encephalit ...201121329775
tackling ebola: new insights into prophylactic and therapeutic intervention strategies.abstract: since its discovery in 1976, ebolavirus has caused periodic outbreaks of viral hemorrhagic fever associated with severe and often fatal disease. ebolavirus is endemic in central africa and the philippines. although there is currently no approved treatment available, the past 10 years has seen remarkable progress in our understanding of the pathogenicity of ebolavirus and the development of prophylactic and post-exposure therapies against it. in vitro and in vivo experiments have shown ...201121349211
involvement of viral envelope gp2 in ebola virus entry into cells expressing the macrophage galactose-type c-type lectin.ebola virus (ebov) infection is initiated by the interaction of the viral surface envelope glycoprotein (gp) with the binding sites on target cells. differences in the mortality among different species of the ebola viruses, i.e., zaire ebolavirus (zebov) and reston ebolavirus (rebov), correspond to the in vitro infectivity of the pseudo-typed virus constructed with the gps in cells expressing macrophage galactose-type calcium-type lectin (mgl/cd301). through mutagenesis of gp2, the transmembrane ...201121362405
[antigenic differences in wild-type and guinea pig-adapted ebola virus strains].the splenocytes isolated from the mice immunized with wild-type or guinea pig-adapted ebola virus strains were used to obtain hybridoma collections. investigation of the monoclonal antibodies (mab) obtained to one of the strains to another revealed antigenic interstrain differences in nucleoprotein and vp40. it is interesting that the differences were found in the hydridoma collection obtained against the wild-type strain. the mabs produced by hydridomas to the adapted strain were found to equal ...201021381339
a new ebola virus nonstructural glycoprotein expressed through rna editing.ebola virus (ebov), an enveloped, single-stranded, negative-sense rna virus, causes severe hemorrhagic fever in humans and nonhuman primates. the ebov glycoprotein (gp) gene encodes the nonstructural soluble glycoprotein (sgp) but also produces the transmembrane glycoprotein (gp1,2) through transcriptional editing. a third gp gene product, a small soluble glycoprotein (ssgp), has long been postulated to be produced also as a result of transcriptional editing. to identify and characterize the exp ...201121411529
lessons learned during active epidemiological surveillance of ebola and marburg viral hemorrhagic fever epidemics in africa.to review epidemiological surveillance approaches used during ebola and marburg hemorrhagic fever epidemics in africa in the past fifteen years. overall, 26 hemorrhagic epidemic outbreaks have been registered in 12 countries; 18 caused by the ebola virus and eight by the marburg virus. about 2551 cases have been reported, among which 268 were health workers (9,3%).201021413569
[study of the functional role of mutation in the guinea pig-adapted ebola virus genome on a drosophila melanogaster model].ebola virus virulence in guinea pigs, which appears through virus adaptation to this animal host, correlates with substitutions in the gene encoding vp24 protein. in particular, the substitution his-->tyr186 was found when obtaining strain 8 ms. an attempt was made to clarify the functional role of this substitution in a transgenic fruit fly model. using the drosophila transformation technique provided transgenic strains that contained genomic insertions of wild-type ebola virus vp24 gene and th ...201121427954
inhibition of ebola virus entry by a c-peptide targeted to endosomes.ebola virus (ebov) and marburg virus (marv) (filoviruses) are the causative agents of severe hemorrhagic fever. infection begins with uptake of particles into cellular endosomes, where the viral envelope glycoprotein (gp) catalyzes fusion between the viral and host cell membranes. this fusion event is thought to involve conformational rearrangements of the transmembrane subunit (gp2) of the envelope spike that ultimately result in formation of a six-helix bundle by the n- and c-terminal heptad r ...201121454542
laboratory detection and diagnosis of filoviruses.ebola virus (ebov) and marburg virus (marv), belonging to the filoviridae family, emerged four decades ago and caused severe viral hemorrhagic fever in human and other primates. as high as 50-90% mortality, filoviruses can cause significant threats to public health. however, so far no specific and efficient vaccine has been available, nor have other treatment methods proved to be effective. it is of great importance to detect these pathogens specific, rapidly and sensitively in order to control ...201121468930
development and characterization of rabbit and mouse antibodies against ebolavirus envelope glycoproteins.ebolaviruses are the etiologic agents of severe viral hemorrhagic fevers in primates, including humans, and could be misused for the development of biological weapons. the ability to rapidly detect and differentiate these viruses is therefore crucial. antibodies that can detect reliably the ebolavirus surface envelope glycoprotein gp(1,2) or a truncated variant that is secreted from infected cells (sgp) are required for advanced development of diagnostic assays such as sandwich elisas or western ...201121513741
tyrosine kinase receptor axl enhances entry of zaire ebolavirus without direct interactions with the viral glycoprotein.in a bioinformatics-based screen for cellular genes that enhance zaire ebolavirus (zebov) transduction, axl mrna expression strongly correlated with zebov infection. a series of cell lines and primary cells were identified that require axl for optimal zebov entry. using one of these cell lines, we identified zebov entry events that are axl-dependent. interactions between zebov-gp and the axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed axl by rnai did n ...201121529875
from the cover: t-cell immunoglobulin and mucin domain 1 (tim-1) is a receptor for zaire ebolavirus and lake victoria marburgvirus.the glycoproteins (gp) of enveloped viruses facilitate entry into the host cell by interacting with specific cellular receptors. despite extensive study, a cellular receptor for the deadly filoviruses ebolavirus and marburgvirus has yet to be identified and characterized. here, we show that t-cell ig and mucin domain 1 (tim-1) binds to the receptor binding domain of the zaire ebola virus (ebov) glycoprotein, and ectopic tim-1 expression in poorly permissive cells enhances ebov infection by 10- t ...201121536871
ebola virus as a foodborne pathogen? cause for consideration, but not panic. 201121571727
replication, pathogenicity, shedding, and transmission of zaire ebolavirus in pigs.background. reston ebolavirus was recently detected in pigs in the philippines. specific antibodies were found in pig farmers, indicating exposure to the virus. this important observation raises the possibility that pigs may be susceptible to ebola virus infection, including from other species, such as zaire ebolavirus (zebov), and can transmit to other susceptible hosts. methods. this study investigated whether zebov, a species commonly reemerging in central africa, can replicate and induce dis ...201121571728
a limited outbreak of ebola haemorrhagic fever in etoumbi, republic of congo, 2005.ebolavirus has caused highly lethal outbreaks of haemorrhagic fever in the congo basin. the 2005 outbreak in the republic of congo occurred in the etoumbi district of cuvette ouest department between april and may. the two index cases were infected while poaching. the sanitary response consisted of active surveillance and contact tracing, public awareness campaigns and community mobilization, case management and safe burial practices, and laboratory confirmation. twelve cases and ten deaths were ...201121605882
depletion of gtp pool is not the predominant mechanism by which ribavirin exerts its antiviral effect on lassa virus.ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is the standard treatment for lassa fever, though its mode of action is unknown. one possibility is depletion of the intracellular gtp pool via inhibition of the cellular enzyme inosine monophosphate dehydrogenase (impdh). this study compared the anti-arenaviral effect of ribavirin with that of two other impdh inhibitors, mycophenolic acid (mpa) and 5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (eicar). all three compounds were ...201121616094
pseudosaccharide functionalized dendrimers as potent inhibitors of dc-sign dependent ebola pseudotyped viral infection.the development of compounds with strong affinity for the receptor dc-sign is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the modulation of the immune response. dc-sign recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. we have previously demonstr ...201121650462
aerosol exposure to zaire ebolavirus in three nonhuman primate species: differences in disease course and clinical pathology.there is little known concerning the disease caused by zaire ebolavirus (zebov) when inhaled, the likely route of exposure in a biological attack. cynomolgus macaques, rhesus macaques, and african green monkeys were exposed to aerosolized zebov to determine which species might be the most relevant model of the human disease. a petechial rash was noted on cynomolgus and rhesus macaques after fever onset but not on african green monkeys. fever duration was shortest in rhesus macaques (62.7±16.3 h) ...201121651988
serologic cross-reactivity of human igm and igg antibodies to five species of ebola virus.five species of ebola virus (ebov) have been identified, with nucleotide differences of 30-45% between species. four of these species have been shown to cause ebola hemorrhagic fever (ehf) in humans and a fifth species (reston ebolavirus) is capable of causing a similar disease in non-human primates. while examining potential serologic cross-reactivity between ebov species is important for diagnostic assays as well as putative vaccines, the nature of cross-reactive antibodies following ebov infe ...201121666792
characterization of the receptor-binding domain of ebola glycoprotein in viral entry.ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. viral entry/infection is initiated by binding of glycoprotein gp protein on ebola virion to host cells, followed by fusion of virus-cell membrane also mediated by gp. using an human immunodeficiency virus (hiv)-based pseudotyping system, the roles of 41 ebola gp1 residues in the receptor-binding domain in viral entry were studied by alanine scanning substitutions. we identified that four re ...201121667336
an enzymatic assay for detection of viral entry.this unit describes a viral entry assay where a beta-lactamase reporter protein fused to the matrix protein of either influenza (blam1) or ebola virus (blavp40) is packaged as a structural component into virus-like particles (vlps). the bla reporter is released upon fusion with target cells and can be detected in live cells by flow cytometry, microscopy, or a fluorometric plate reader for utility in high-throughput screening approaches. the transfer of bla to a target cell by blam1 or blavp40 vl ...201121688257
structure and function of the complete internal fusion loop from ebolavirus glycoprotein 2.ebolavirus (ebov), an enveloped virus of the family filoviridae, causes hemorrhagic fever in humans and nonhuman primates. the viral glycoprotein (gp) is solely responsible for virus-host membrane fusion, but how it does so remains elusive. fusion occurs after virions reach an endosomal compartment where gp is proteolytically primed by cathepsins. fusion by primed gp is governed by an internal fusion loop found in gp2, the fusion subunit. this fusion loop contains a stretch of hydrophobic residu ...201121690393
[ebola and marburg hemorrhagic fever viruses: update on filoviruses].the ebola and marburg viruses are the sole members of the filoviridae family of viruses. they are characterized by a long filamentous form that is unique in the viral world. filoviruses are among the most virulent pathogens currently known to infect humans. they cause fulminating disease characterized by acute fever followed by generalized hemorrhagic syndrome that is associated with 90% mortality in the most severe forms. epidemic outbreaks of marburg and ebola viruses have taken a heavy toll o ...201121695865
ebolavirus {delta}-peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry.with the exception of reston and lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans. filoviruses use a class i fusion protein, gp(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. in addition to gp(1,2), ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble gp (sgp) and small soluble gp (ssgp). all three glycoproteins have identical ...201121697477
ebola and marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for africa.ebola and marburg viruses are the only members of the filoviridae family (order mononegavirales), a group of viruses characterized by a linear, non-segmented, single-strand negative rna genome. they are among the most virulent pathogens for humans and great apes, causing acute haemorrhagic fever and death within a matter of days. since their discovery 50 years ago, filoviruses have caused only a few outbreaks, with 2317 clinical cases and 1671 confirmed deaths, which is negligible compared with ...201121722250
functional genomics reveals the induction of inflammatory response and metalloproteinase gene expression during lethal ebola virus infection.ebola virus is the etiologic agent of a lethal hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. previous studies with zaire ebola virus (zebov), mouse-adapted virus (ma-zebov), and mutant viruses (zebov-np(ma), zebov-vp24(ma), and zebov-np/vp24(ma)) allowed us to identify the mutations in viral protein 24 (vp24) and nucleoprotein (np) responsible for acquisition of high virulence in mice. to elucidate specific molecular signatures associated with lethality, we ...201121734050
current perspectives on the phylogeny of filoviridae.sporadic fatal outbreaks of disease in humans and non-human primates caused by ebola or marburg viruses have driven research into the characterization of these viruses with the hopes of identifying host tropisms and potential reservoirs. such an understanding of the relatedness of newly discovered filoviruses may help to predict risk factors for outbreaks of hemorrhagic disease in humans and/or non-human primates. recent discoveries such as three distinct genotypes of reston ebolavirus, unexpect ...201121742058
isolation and characterisation of ebolavirus-specific recombinant antibody fragments from murine and shark immune libraries.members of the genus ebolavirus cause fulminating outbreaks of disease in human and non-human primate populations with a mortality rate up to 90%. to facilitate rapid detection of these pathogens in clinical and environmental samples, robust reagents capable of providing sensitive and specific detection are required. in this work recombinant antibody libraries were generated from murine (single chain variable domain fragment; scfv) and nurse shark, ginglymostoma cirratum (ignar v) hosts immunise ...201121752470
an alternative method of measuring aerosol survival using spiders' webs and its use for the filoviruses.understanding the ability to survive in an aerosol leads to better understanding of the hazard posed by pathogenic organisms and can inform decisions related to the control and management of disease outbreaks. this basic survival information is sometimes lacking for high priority select agents such as the filoviruses which cause severe disease with high case fatality rates and can be acquired through the aerosol route. microthreads in the form of spiders' webs were used to capture aerosolised fi ...201121762730
reston ebolavirus antibodies in bats, the philippines.to the editor: filoviruses cause highly lethal hemorrhagic fever in humans and nonhuman primates, except for reston ebolavirus (rebov), which causes severe hemorrhagic fever in macaques (1,2). rebov epizootics among cynomolgus macaques occurred in 1989, 1990, 1992, and 1996 (2) and among swine in 2008 (3). african fruit bats have been suggested to be natural reservoirs for zaire ebolavirus and marburg virus (4-6). however, the natural reservoir of rebov in the philippines is unknown. thus, we de ...201121801651
usa focuses on ebola vaccine but research gaps remain. 201121809495
inactivated or live-attenuated bivalent vaccines that confer protection against rabies and ebola viruses.the search for a safe and efficacious vaccine for ebola virus continues, as no current vaccine candidate is nearing licensure. we have developed (i) replication-competent, (ii) replication-deficient, and (iii) chemically inactivated rabies virus (rabv) vaccines expressing zaire ebola virus (zebov) glycoprotein (gp) by a reverse genetics system based on the sad b19 rabv wildlife vaccine. zebov gp is efficiently expressed by these vaccine candidates and is incorporated into virions. the vaccine ca ...201121849459
Lethality and pathogenesis of airborne infection with filoviruses in A129 a/ß -/- interferon receptor-deficient mice.Normal immunocompetent mice are not susceptible to non-adapted filoviruses. There are therefore two strategies available to establish a murine model of filovirus infection: adaptation of the virus to the host or the use of genetically modified mice that are susceptible to the virus. A number of knockout (KO) strains of mice with defects in either their adaptive or innate immunity are susceptible to non-adapted filoviruses. In this study, A129 a/ß -/- interferon receptor-deficient KO mice, strain ...201221852521
differential requirements for clathrin endocytic pathway components in cellular entry by ebola and marburg glycoprotein pseudovirions.clathrin-mediated endocytosis was previously implicated as one of the cellular pathways involved in filoviral glycoprotein mediated viral entry into target cells. here we have further dissected the requirements for different components of this pathway in ebola versus marburg virus glycoprotein (gp) mediated viral infection. although a number of these components were involved in both cases; ebola gp-dependent viral entry specifically required the cargo recognition proteins eps15 and dab2 as well ...201121855102
A replicating cytomegalovirus-based vaccine encoding a single Ebola virus nucleoprotein CTL epitope confers protection against Ebola virus.Human outbreaks of Ebola virus (EBOV) are a serious human health concern in Central Africa. Great apes (gorillas/chimpanzees) are an important source of EBOV transmission to humans due to increased hunting of wildlife including the 'bush-meat' trade. Cytomegalovirus (CMV) is an highly immunogenic virus that has shown recent utility as a vaccine platform. CMV-based vaccines also have the unique potential to re-infect and disseminate through target populations regardless of prior CMV immunity, whi ...201121858240
Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection.Ebola virus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the identificat ...201121866101
ebola virus entry requires the cholesterol transporter niemann-pick c1.infections by the ebola and marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. filovirus entry is mediated by the viral spike glycoprotein (gp), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these c ...201121866103
Crystal structure of swine major histocompatibility complex class I SLA-1 0401 and identification of 2009 pandemic swine-origin influenza A H1N1 virus cytotoxic T lymphocyte epitope peptides.The presentation of viral epitopes to cytotoxic T lymphocytes (CTLs) by swine leukocyte antigen class I (SLA I) is crucial for swine immunity. To illustrate the structural basis of swine CTL epitope presentation, the first SLA crystal structures, SLA-1 0401, complexed with peptides derived from either 2009 pandemic H1N1 (pH1N1) swine-origin influenza A virus (S-OIV(NW9); NSDTVGWSW) or Ebola virus (Ebola(AY9); ATAAATEAY) were determined in this study. The overall peptide-SLA-1 0401 structures res ...201121900158
Genus-specific recruitment of filovirus ribonucleoprotein complexes into budding particles.The filoviral matrix protein VP40 orchestrates virus morphogenesis and budding. To do this it interacts with both the glycoprotein (GP1,2) and the ribonucleoprotein (RNP) complex components; however, these interactions are still not well understood. Here we show that for efficient VP40-driven formation of transcription and replication-competent virus-like particles (trVLPs), which contain both an RNP complex and GP1,2, the RNP components and VP40, but not GP1,2 and VP40, must be from the same ge ...201121900424
the ebola virus glycoprotein mediates entry via a non-classical dynamin-dependent macropinocytic pathway.ebola virus (ebov) has been reported to enter cultured cell lines via a dynamin-2-independent macropinocytic pathway or clathrin-mediated endocytosis. the route(s) of productive ebov internalization into physiologically relevant cell types remain unexplored, and viral-host requirements for this process are incompletely understood. here, we use electron microscopy and complementary chemical and genetic approaches to demonstrate that the viral glycoprotein, gp, induces macropinocytic uptake of vir ...201121907381
characterization of zaire ebolavirus glycoprotein-specific monoclonal antibodies.zaire ebolavirus (zebov) can be transmitted by human-to-human contact and causes acute haemorrhagic fever with case fatality rates up to 90%. there are no effective therapeutic or prophylactic treatments available. the sole transmembrane glycoprotein (gp) is the key target for developing neutralizing antibodies. in this study, recombinant vsvδg/zebovgp was used to generate monoclonal antibodies (mabs) against the zebov gp. a total of 8 mabs were produced using traditional hybridoma cell fusion t ...201121925951
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